Out-Of-Hospital Cardiac Arrest Clinical Trial
Official title:
Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest - a Randomized Clinical Trial
Resuscitated cardiac arrest is associated with a systemic inflammatory response that is directly associated with poor prognosis. Inhibition of the IL-6 mediated immune response may potentially inhibit the systemic inflammatory response, potentially improving the prognosis of these severely ill patients.
INTRODUCTION AND BACKGROUND:
The incidence of out-of-hospital cardiac arrest (OHCA) in Denmark is approximately 4,000 per
year, and the mortality remains approximately 90%. Furthermore, in the approximately 30% of
patients who are resuscitated and admitted to the intensive care unit (ICU), the mortality
within the first month remains between 50% to 70%. Accordingly, an increasing emphasis on
post-resuscitation care has been addressed by contemporary guidelines.
The high mortality after resuscitated OHCA has been attributed to a post-cardiac arrest
syndrome (PCAS), which includes four mutually interacting components: a systemic inflammatory
response (SIRS)-like syndrome, cerebral injury, myocardial dysfunction, and the persistent
precipitating cause of the arrest. Despite repeated emphasis on post-resuscitation care, no
specific therapies targeting PCAS have been implemented, with the exception of targeted
temperature management (TTM), which has been recommended since 2003. Accordingly, research
addressing mitigation of the PCAS seems intuitively beneficial.
During and after OHCA, exposure to whole-body ischemia and reperfusion injury triggers
activation of inflammatory cascades leading to a sepsis-like syndrome. A multitude of
inflammatory markers have been associated with unfavorable outcome after OHCA, including
procalcitonin (PCT), c-reactive protein (CRP), interleukin (IL) 6, and IL-10.
Furthermore, the inflammatory markers interleukin 1β (IL-1β), IL-6, IL-10, and tumor necrosis
factor α (TNF-α) have all been associated with the severity of PCAS, assessed by sequential
organ failure assessment (SOFA) score. Importantly, levels of IL-6 have been shown to be
independently associated with unfavorable outcome after adjustment for known risk markers.
Further, the level of IL-6 was more strongly associated with PCAS severity compared to
classical inflammatory markers such as CRP and PCT.
Interleukin-6 is a pro-inflammatory cytokine secreted by T cells and macrophages. IL-6
readily crosses the blood-brain-barrier and is a mediator of fever. Further, IL-6 is a
mediator of the acute phase response and plays a role in activation of the coagulation
system, increasing vascular permeability, and weakening papillary muscle contractions leading
to myocardial dysfunction. As such, IL-6 is involved in pathological processes including
tissue hypoxia, disseminated intravascular coagulation (DIC), and multiorgan failure, all of
which represent parts of the SIRS response. IL-6 has been suggested to play a role in
ischemia-reperfusion injury in myocardial infarction (MI), and higher levels of IL-6 have
been associated both with the magnitude of myocardial injury, mortality and adverse events in
this group.
Due to the role of IL-6 in many inflammatory diseases, IL-6 receptor antibodies (IL-6RA) have
been developed. The first IL-6RA, tocilizumab, was approved for treatment of rheumatoid
arthritis in 2009, and has later been approved for giant cell arthritis and chimeric antigen
receptor (CAR) T cell-induced cytokine release syndrome. In addition to the approved
indications, tocilizumab has been suggested to have other beneficial immune modulating and
organ protective effects.
In patients presenting with non-ST-elevation myocardial infarction (NSTEMI), a one-hour
infusion of 280mg tocilizumab decreased the inflammatory response assessed by CRP levels, and
further decreased myocardial injury assessed by TnT levels. Importantly, no increased risk of
adverse events was observed in patients receiving tocilizumab. Animal data suggest that
tocilizumab is safe and effective for treatment of severe acute pancreatitis and associated
acute lung injury. Further, tocilizumab had neuroprotective effects in a model of Alzheimer
disease. In humans, tocilizumab has been suggested to be effective against the autoimmune
neurological disorders neuromyelitis optica and autoimmune encephalitis.
In summary, resuscitated OHCA is associated with a severe SIRS-like response, the magnitude
of which has been associated with increased mortality and poor neurological outcome.
Inhibiting the IL-6 mediated immune response may inhibit the SIRS-like response and may
further inhibit ischemia-reperfusion injury leading to improved outcome.
HYPOTHESIS:
A one-hour infusion of the IL-6RA tocilizumab initiated as soon as possible after ROSC will
reduce the SIRS-like response assessed by hsCRP levels after OHCA.
SAMPLE SIZE:
A total of 80 patients will be included, i.e. 40 being allocated to IL-6RA and placebo,
respectively. Patients who die or become hemodynamically unstable immediately after
randomization before the study drug has been prepared will be excluded from the modified
intention to treat population and replaced by randomizing additional patients. Likewise,
patients for whom the relatives refuse study participation when informed of the study and
asked for consent (before the patients can be asked) will be excluded from the modified
intention to treat population and replaced.
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